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α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease.

ABSTRACT:

Background

Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown.

Methods

We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days.

Results

Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation.

Conclusions

Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

SUBMITTER: Hering L

PROVIDER: S-EPMC7191918 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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<i>α</i>2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease.

Hering Lydia L Rahman Masudur M Hoch Henning H Markó Lajos L Yang Guang G Reil Annika A Yakoub Mina M Gupta Vikram V Potthoff Sebastian A SA Vonend Oliver O Ralph Donna L DL Gurley Susan B SB McDonough Alicia A AA Rump Lars C LC Stegbauer Johannes J

Journal of the American Society of Nephrology : JASN 20200221 4

<h4>Background</h4>Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional <i>α</i>2A-adrenoceptors on sympathetic nerves, and <i>α</i>2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of <i>α</i>2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown.<h4>Methods</h4>We inv ...[more]

PMID: 32086277

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